The present invention, in some embodiments thereof, relates to novel acyl-urea containing compounds, and to uses of acyl-urea containing compounds in a variety of therapeutic applications, including, for example, neurological diseases and disorders such as epilepsy, neuropathic pain and bipolar disorders.
Epilepsy, also referred to in the art as a seizure disorder, is a chronic disorder of the central nervous system (CNS), characterized either by recurrent and unprovoked episodic loss of attention or sleepiness or by severe convulsions with loss of consciousness called seizures or fits. The seizures are considered as transient symptoms which are attributed to irregular immoderate or coincident neuronal activity in the brain. This incurable yet typically therapeutically controlled medical condition affects about 0.5% of the population, whereas about 1.5-5.0% of the population may have a seizure in their lifetime at any age.
Prolonged seizures may lead to the development of Status epilepticus (SE), which is a life threatening cerebral state of a persistent seizure. SE can be defined broadly as one continuous seizure or a series of recurrent seizures wherein the subject does not regain consciousness between seizures for longer than 30 minutes. It is believed that 5 minutes are sufficient to cause irreparable damage to the neurons, and in SE cases seizures are unlikely to terminate spontaneously by that time. In a subject known to suffer from epilepsy, SE can be brought about or be aggravated by poor compliance to treatment (adherence to medication regimen), alcohol withdrawal and/or metabolic disturbances. As a primary presentation it may indicate a brain tumor or abscess. SE was also reported to be caused by various nerve agents (organophosphates) such as sarin, VX and soman.
Current treatment of epilepsy typically consists of oral administration of anticonvulsants or antiepileptic drugs (AEDs). This symptomatic treatment is aimed at reducing the number and severity of future seizures. The efficacy of AEDs depends on the patient's response to a particular AED, which in turn is selected according to the type and severity of the seizure. Some epileptic patients are known to respond well to one AED and may respond poorly or even worsen the condition by others. When the epileptic condition seems not to respond to the use of AEDs, it is referred to as “refractory epilepsy”, which is typically treated by brain surgery to remove the abnormal brain cells that are causing the seizures, or by a vagal nerve stimulator, which is implanted in the chest, which helps reducing the number of seizures.
Four major antiepileptic drugs (AEDs) are currently used for the treatment of epilepsy (epileptic seizures and convulsions), which include phenyloin (marketed as Dilantin® in the USA and as Epanutin® in the UK), carbamazepine (sold under the brand-names Biston, Calepsin, Carbatrol, Epitol, Equetro, Finlepsin, Sirtal, Stazepine, Tegretol, Telesmin, Timonil), phenobarbital (also known as phenobarbitone or Luminal®) and valproic acid (VPA). However, about 25% of the patients do not respond to the current medications. Furthermore, AEDs are administered repetitively as chronic treatment and the adverse effects associated with antiepileptic therapy are of a major concern. The major established AEDs are associated with some rare but severe side effect such as teratogenicity and other adverse effects that limit their use.
Status epilepticus is typically treated with benzodiazepines such as diazepam, clonazepam, lorazepam phenobarbital, phenyloin and lorazepam. Phenyloin and it's prodrug fosphenyloin as well as other hydantoin derivatives are also used to treat SE, and are typically co-administered with a benzodiazepine phenobarbital or barbiturate. Barbiturates such as phenobarbital, secobarbital, thiopental or pentobarbital, are still used today to treat SE if benzodiazepines or the hydantoins are not an option, primarily by induction of a barbituric coma. In that respect of coma-causing agents, general anesthetics such as propofol and lidocaine are used where barbiturates are ineffective or cannot be used for some other reason.
Valproic acid is a broad-spectrum antiepileptic and CNS active agent, which is still in use as an anticonvulsant and mood-stabilizing drug in the treatment of epilepsy and bipolar disorder. It has also been used in the treatment of neuropathic pain, myoclonus, schizophrenia and for migraine prophylaxis. VPA is believed to act through a combination of mechanisms, namely as a membrane stabilizer; as a GABA transaminase inhibitor, thereby enhancing GABA signaling; and as a serotonergic inhibitor which reduces NMDA-receptor mediated glutamate excitation. In principle, such multilevel action is highly advantageous, promising improved efficacy with reduced side effects. However, the clinical use of VPA is limited by two rare, but potentially life-threatening side effects, teratogenicity and hepatotoxicity that restrict its utilization in women of child bearing age and in children. While VPA's teratogenicity is associated with the parent compound [1], its hepatotoxicity results from biotransformation into hepatotoxic metabolites with a terminal double bond, specifically 4-ene-VPA [2-4].
Extensive efforts have therefore been directed towards therapeutically active derivatives of VPA which exhibit improved activity and/or reduced side effects.
Therapeutically active derivatives of VPA include the salt sodium valproate which is used in anticonvulsant formulations, and valproate semisodium, which is used as an anticonvulsant and a mood stabilizer. A homologue of VPA wherein one of the alkyl chains is three carbons longer, arundic acid ((R)-(−)-2-propyloctanoic acid, also known as ONO-2506), is currently under clinical development for the potential treatment of stroke, as well as of other neurodegenerative diseases including amytrophic lateral sclerosis (ALS), Alzheimer's disease and Parkinson's disease [5].
A series of VPA-amide analogue and derivatives thereof was developed via a series of structure (pharmacokinetic/pharmacodynamic) activity relationship studies, and were found to exhibit improved anticonvulsant activity while avoiding teratogenicity and hepatotoxicity [6-9]. Some of these VPA amide derivatives were also active in animal models of neuropathic pain [10, 11] and bipolar disorder [12, 13].
Urea is an integral part of the heterocyclic chemical structures of three leading AEDs, namely phenobarbital, phenyloin and carbamazepine. These drugs consist of a lipophilic moiety delineated by phenyl-alkyl in phenobarbital, diphenyl in phenyloin and dibenzazepine in carbamazepine, and a hydrophilic moiety, containing a ring fused urea molecule. The presence of urea in all of these drugs implies that it plays an important role in the anticonvulsant pharmacophore [6, 14].
Acyl-urea containing compounds are known for many decades [15-18]. These compounds have been considered promising anticonvulsants [19] and as sedative or hypnotic agents [20]. Spielman and coworkers [19] synthesized a series of acyl-urea derivatives using a variety of branched aliphatic and aromatic residues, and evaluated as potential anticonvulsant agents using maximal electroshock seizure test (MES) and subcutaneous metrazol test (scMet) in mice. In this series, Spielman reports that several derivatives of acyl-urea demonstrated potent anticonvulsant activity, including 2-ethyl-3-methylvalerylurea, 2-ethylcaproylurea and 2-isopropyl-Δ4-pentenoylurea, whereby other derivatives were found non-active. The anticonvulsant profile of valproylurea was also evaluated by Tantisira et al. [21] on mice MES and scMET models, who showed an excellent protection in both models with a favorable protective index compared to valproic acid.
Other acyl-urea containing compounds have been previously reported and studied as drugs for the treatment of psychiatric and neurological conditions. An example is the drug Sedormid (allyl-isopropyl-acetyl urea) which was used as a mild anxiolytic and sedative agent until it was found toxic and therefore is no longer marketed.
U.S. Pat. No. 3,282,998 teaches the synthesis of (2-ethyl-3-methyl-pentanoyl)-urea, and Goldstein et al. [22] reported studies relating to this compound, known as the drug Capuride (Pacinox®) which was indicated for sleep disorders, as a minor tranquilizer and anti-anxiety agent. None of these publications relates to the stereochemistry of the compound.
One of the observations which stem from these seminal studies is the effect of seemingly minor structural changes in the acyl group, such as the location, addition or elimination of even a single methyl group or more, on the activity of the resulting compound.
A new and highly effective AED, 2,2,3,3-tetramethylcyclopropylcarbonylurea, has recently been synthesized and tested [6]. This acyl-urea derivative of cyclopropane showed anticonvulsant activity in both the scMet and the MES model tests in mice and rats [23], with a protective index, e.g. median neurological toxic dose to median effective dose ratio (TD50-to-ED50 ratio) of 18.5 in the MES test, compared to 1.6 which was measured and calculated for valproic acid.
U.S. Pat. No. 6,417,399 by two of the present inventors relates to the individual stereoisomers of the drug valnoctamide (a mixture of four stereoisomer kinds of 2-ethyl-3-methyl-pentanamide, VCD) which are shown to be more potent than any mixture thereof in the treatment of neurological and psychotic disorders such as epilepsy, pain and affective disorders, and useful as tranquilizers. This disclosure further teaches a method for stereoselective separation and quantification of each of the four stereoisomers from a racemic mixture of VCD or from plasma of patients treated with the racemic drug, and to a unique method for the synthesis of the individual stereoisomers.